Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating disorder that is broadly distributed in the US population. It is defined by a fearful response to traumatic events, and involves reexperiencing, arousal, and avoidance of reminders of the traumatic exposure. Despite efforts to characterize the pathophysiology of PTSD, no biomarkers currently exist to facilitate diagnosis, treatment development, or prediction of treatment response. Yet several lines of evidence suggest that PTSD symptoms are mediated by dysfunctional processes involving the brain's fear-circuitry network. It is not known, however, whether failure to recover from PTSD is governed by functional deficits in this circuitry. The proposed five year interdisciplinary project will clarify circuits underlying PTSD psychopathology and probe, for the first time, neural circuitry of symptomatic improvement in response to prolonged exposure (PE) treatment of PTSD. Our goals are congruent with NIMH strategic plan strategy 1.3 to identify and integrate biological markers and behavioral indicators associated with mental disorders. The project builds directly on our preliminary work in assessing deficits in extinction learning and recall by applying a basic science fear extinction paradigm to trauma-exposed healthy controls and patients with PTSD. The proposed study will employ an established extinction paradigm with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) assessments in a large and well characterized sample of patients with PTSD and trauma exposed healthy control (TE-HC) subjects. One hundred subjects including 60 individuals with PTSD and 40 trauma exposed healthy controls will be assessed by fMRI and SCR to characterize neural circuitry activation to the fear extinction task. fMRI and SCR data will be acquired simultaneously during this two-day emotional learning task. All 60 PTSD and 20 randomly assigned TE-HC participants will repeat these procedures after PTSD patients have completed 10 weeks of intensive PE treatment. Clinical ratings of PTSD severity will be conducted three months after treatment completion to permit analysis of neural predictors of longer-term treatment durability. The project will yield new insights and information concerning the neural circuitry that underlies identified extinction deficiencies that characterize PTSD. It will also provide vitally important new information concerning the neural effects of PE treatment, a first line treatment for PTSD. Together these lines of research will not only advance the identification of biomarkers for PTSD, but also facilitate identification of biomarkers of clinical response to this empirically-supported treatment that may guide future treatment development of pharmacological adjuncts to PE and novel methods for enhancing extinction processes among patients with PTSD.